3, 11-diketo-20, 21-dioxypregnanes and process



Patented July 25,1950 2,516,258

UNITED STATES PATIENT OFFICE 3,11-DIKET-20,21-1)I0XYPREGNANES ANDPROCESS Lewis H. Sarett, Princeton, J assiignor to Merck & Co., Inc.,Rahway, N. J a corporation of New Jersey "No Drawing. Application August2, 1946, SerialNo. 687,980

vis,(tim s; (c1. zen-397.4) 1 t j I M 2 z This invention is concernedgenerally with purpds'es ofioonvenience is hereinafter reproduced novelchemical compounds of the cyclopentaiio- 1 below in the'abbreviatedform: 1 dimethylpolyhydrophenanthrene series andproc'- esses forpreparing the same; more particularly it W a 3 relates to stereoisomersof 3,11-diketo-20,21-di- 6 0H. 0H; H R I hydroxy-pregn-ane and acylatedderivatives there-- of and with methods of manufacturing thfse compoundsfrom readily available startiiigillaterials. It is further concernedwith'methogls of isolating said stereoisomers, namely 3; 1 1 diketoa)-21-dihydroxy-pregnane and 3';l 1"-"dike'to- 20-(B)-2l-dihydroxy-pregnane and their? acQL- ated derivatives insubstantially pure form". The new compounds thus produced are of valuein the preparation of the adrenal hormones suchas dehydrocorticosterone, dehydrocorticosterone esters, and for other purposes.They are also of value as a means of establishing the structure of!other organic compounds.

These stereoisomeric 3,11 -dil eto -20,2 1-vdihydroXy-preg'nanes andtheir acvl'ated derivatives}- subject of this application; caribrepresented by" the following structural formulae:

I ZICHHOR 20H- -03 19 H2 OH: \l/ 0 13 2 1av CH: 1) H2 14 15 kl/9a He H1mcz 10 son" A I B .Ls, 'a ill-1- J, a i hdr.. X l9r, W H1tlrec'm'carbcsfi sid" f:l'iaii1- thus.

05-3: 0 I Ha Ha a r ,l 1 l v 0 H3 2 and lin thescasef-iof r epimeric a'coniiguratiomathe 5*; subst-ithent -isr*writtemtmthe"leftside ofithevsidc \l/ chain thus: O=C CH: a a OH I emom Hg! 3 c C .H l I a (a)Theistreoche'mical rlatienshipofirlfi a: l a and B is indicated in theformulae byasolid i representing the valence bondin the ci's config- C/HTS/b10111 I 5 N v g. In-'accordanc"with the-present 'inventiorr; it is}H now: foundthat '3,1 1-diketo-20;2-1-dihydr wherein-Ris hydrogenortacyl x This formula-for p es me andwcylatetlderivatives theredf can?be synthesized by reactions represented generi- Accordingly, I prefer toreact said mixture of cally as follows: A 3,1l-diketo-pregnene and A-3,11-diketoom OHIOH I I p ore onion CH; 110-- -H t 1 OH: t H-OH Osmiumi" Tetroxide I r (3)- o i o I H V l Alt Hydrolysis] [A2231 mg{Hydrolysis I on, cmon on. GHi o-R l. I, I on, RO-(J-H om H- .s-on Hwherein R is an acyl group, pregnene (6);which can be represented by'theThe reactions indicatedabove are conducted as following'structuralformulae; follows: The starting material A -3,11-diket0- Y 1 m pregnene(1) which can be :prepared as disclosed in my co-pending applications,Serial'No. 649,760, A V I filed February 23, 1946 (which is acontinuation in partipf application Serial No. 605,194, filed July 14,l935,' n ow abandoned); and SeriaTNo." 687,982, fiie 'pAugu tz'; 1946,how Patent No. 2,505,838; is reactedlwithan agent capable ofconvertingan olefini'cbohdto'the corresponding glycol, such as,

tetroxide, or hydrogen peroxide in contactwitha'catylytic amount ofosmium tetroxide, Q whereby the ethylenic linkage is converted to the vcorresponding glycol to produce a mixture of the stereois'omeric3,1'1-diketo' 2001) ,ZI-dihydroxy t CH pregnane" (2) and -3,'1l;.-diketo-2q(fi) 21-dihy 5 droxy-pregnane (3')". Thi's'mixture of isomers'is' i 4 H reacted with an acylating agent to form the cor- 0 Hresponding mixture of stereoisomers of 3,11-diketo-20,2l-diacyloxy-pfegnane (4 and 5). a I These isomers can beseparated from each other, 30 as' for example, by means ofchromatographic adsorption tos'produce thestereoisomers of13,11-diketo-20-(a) -21-diacyloxy-pregnane '-'-(4) i and3,11-diketo-20-(B)-21-diacyloxy-pregnane (5) in i substantially pureform. i These pure stereoisoi i mers can then be hydrolyzed to producethe cord1 rect1y osntmm F P 15 accom' responding pure isomers 311 diketo20 (a) plished by dissolving said mixture 1n asubstand'ihydroxy-pregnane "(2)1 and"3"11 dik t 20 ([3) tially inertsolvent, as ior example, a dialkyl ether zldihydroxwpregnane V i, i ysuch as ethyl ether, and adding a solution of .i when the startingmaterial, said 2o,21 3 11 7o osmium tetroxide thereto. Atertiary amine,such diketo-pregnene (l) is prepared according to-the as Pyrldine, qinoline, picoline, and the l e, y processes described in'my co-pendingap li ation then be added to this solution and the mixturealhereinabove-referred to, it is obtained admixed lowed to reactpreferably at a temperature bewith the correspondin A1 7! -isomer,-compound E tweenabout O -and 20C. The reaction mixture 6 below, fromwhich it is not readily separated. is allowed to stand for considerabletime at about masseus 5 OZtfit to:completescrystallizatiomofi'the:osmate aa esters whichzaretremoved.:by;.filtration-anditheni hydrolyzedibwtreatingiwith anaqueousasolutiom of an alkaline reducing, agent, asfor example, sodiumpsulfite. The hydrolysis mixture is filtered andithe;filtrate evaporated to small volumexand theznmixtureof stereoisomericglycols extracted therefrom by means of a chlorinated a hydrocarban.solvent} such sis-chloroform; ethylene cliel rt v lucid and the-like;the solvent is tlien evapo--- rated to=- produce a crude mixturecontaining: 3. 11 diket'o 20(a) 21-=dihydroxy-pregnane- ('21)), 34diketo 20"- (pf- 21 dihydrox-y -pregnanef The mixture 'ofz idiketodihydroxy--pregnanes. is i then treated with a cyclicaanhydride of adicarboxylic acid, as for example, succinic anhydride orgplithalicanhydridei The reaction can be conducted at-"room temperature, butisbest carried out; y lieating the reactants at about- 90-100 irr tliepresence of an an1 1ydrcpus;alkaline'medium; p

'rab1ya tertiary amine such as pyridine ,olinefpicol-ine and thelikewhereby-the pfl m p ydroxyl groupspresent in'the-sterecisemers of3%11-diketo-20,2l dihydroxy pregnane are preferentially esterifi'ecl:The reaction mixture--- mam-med Witlr'water to destroy unreacted anhyarms; and the' resultin mixture is evaporated stfistantially to'dryness,preferably underreduced- 5c pressure. The residuahmaterial, whichconsists ofitlie; isomeric- 31 1 1 -Vdiketo'-20-liydroXy=21- (car buxyacyloxy) pregnane L admixed witli unesterl new 3; 11 dik'et017;20=dihydroxy pregnane is;- treatedtwith an" aqueous alkalinesolutionsuehe 7o 3, as;;;aqueous-@sodiumcarbonate solution and fa;water-immiscible solvent,- such: as a chlormated hydtocarbonssolvent ahydrocarbon sol-ventp-and thee Ker The-aqueous 1ayer whichcontains-"thee saitsiofitlie haltiesters ot the desired l'stereoisoaa75;

6%? m ri'c 3;11. '+dike.to-.20}*2isdihrdroxys-tpreenanee is separated;from theanoneaqueous 's solution- .-whic containsfthe:lwzmdihydroxyisomer; Th"

leagues ous; solution is then acidifiediwith-an' .aqueous;.- sq= lutionofsa; mineral 1 acid and; the 1 stereoisomerig v; halfesters, 3;111-diketm20-(u) fhYdrOXYf'ZLPICaR-F boxy-acylcxy) -pregnane1(8);and,3f, 11;diketo-,20 (pix-21+ (carboxmacyloxy) -pregnane 5(9),;are.-.ex. tracted. therefrom, withvqat solvent? oft; the-a-claspreviously mentioned. Evaporation; oi' ithisi 91-;

ventextractyieldsamixturezofrtheseahalf esterswhichz-cansbeirepresentedaby the followinggstru tural formulae whereinBi. isaan alkylenegarylene or, aralkyl enegg radicals This .product; canbe hydrolyzed by; any; cont. venient method'as fortexample, Joy.reacting-,zwithq, an aqueous valkaline solution ,to produce tlielcor=responding mixture 4 off; thestereoisomeric 3,111; diketo-20=(a) ,2l.-pdihydroxyo-pr egnane. (2),; an dj f, ,1. ediket0 -2 I l dihy ro =prna ee 11'. substantially free. of J the., .3 ,lI -Vdi ketov-I'LZOQdihyg; 1: droxy pregnane isomer. v

Thislmixture .of ,stereoisomers isireacted'lwitii n: xce s; f..,anacrlain e ntmpref ably in hetpre encevof ate tiarx: ami ersuchiasipyii ii klquinoline, ,picoline =and1the like to, form the .co responding mixtureof stereoisomers of '3',11-dil eto-20,21-diacyloxy-pregnane--representedby the follow-ingstructural.formulatt,

wherein R is acyl. Among the acylating' agents which are useful for thispurpose,arealiphatic. anhydrides such as acetic anhydride, propionicanhydride, butyric anhydride, valeric anhydride and the like, organicacyl halides such as acetyl chloride, propionyl chloride, butyrylchloride,

drideis preferred. 1

The mixture of-the stereoisomers. of. 3,11-

diketo-20,2l-diacyloxy pregnane can be converted.- without furtherpurification to an ester. of dehydrocorticosterone, but it is presentlypreferred to separate these epimers from each other and in substantiallypure form. This can be accomplished by any convenient means, as forexample, by fractional crystallization or by chromatographic absorptionfrom a hydrocarbon solvent such as benzene, toluene, solventnaphthapetroleum ether, and the like, or preferably from a mixture ofsolvents such as'benzene-petroleum ether. The absorbing medium employedcan' be any of those commonly used for this purpose, but it is presentlypreferred to use activated alumina; the epimeric pregnane compounds arepreferentially eluted from the absorbent by'means of a selectivesolvent, such as a: mixture of ether petroleum ether followed byether-chloroform. The individual epimers separated in this way arepurified by recrystallization from a solvent such as acetone, aqueousacetone, ether "or lower aliphatic alcohols. I 1

The individual epimeric 3,11-diketo-20,2li-'diacyloxy-pregnane obtainedas described above, can be converted to the corresponding epimers of 3,11- diketo'-'20;21 -'dihydroxy-pregnane by reaction with a hydrolyzingagent under saponifying conditions. Hydrolyzing agentsoperable in'applicants process include alkali or alkaline earth hydroxides, alkalicarbonates or bicarbonates', mineral acids, and thelike which can beused in Water or aqueous organic solvent solution; it is presentlypreferred to employ an aqueous methanol solution containing potassiumcarbonate and potassium bicarbonate.

The following examples illustrate methods of carrying out thepresentinvention, but it is to be understood that these examples are givenfbyway of illustration and not of limitation. v I Example! About 9.65 g. ofamixture-'containingn and A -3,ll-diketo pregnene is dissolved in about50 cc. absolute ether and a solution containing about 8.0 g. ofosmiumtetroxide in about 50 cc. of absolute ether is added thereto.About 2.4 cc. of pyridine isjthen added and the mixture is allowed tostand at about 20 C. for approximately 1 hour and thenat-about C. forapproximately 36 hours. The precipitated osmate esters are removed byfiltration, suspended in about 350 cc. of alcohol and a solution ofabout 55 g. of sodium sulfite in about 240 cc. of hot water is addedthereto and the mixture refluxed for approximately 3 hours. The mixtureis then filtered'and the insoluble material extracted twice withapproximately 200cc. portions of hot alcohol and the alcohol"extractscombined with the initial filtrate. This filtrate is then evaporatedunder reduced pressure to a small volume, diluted with water andextracted with chloroform. The chloroform layer is washed with water andevaporated to dryness under reduced pressure to produce a, crude mixturewhich contains"3.l1 diketo 17,20 3,11'-diket0-20- (a)-21'-dihydroxy-pregnane. 3,ll'-'diketo-20-(p) Esrample 2 Theseparationof 3,1l-diketo-17,20-dihydroxy-. pregnane from the stereoisomeric3,11-diketo- 20,2l-dihydroxy-pregnanes is achieved by dis solving about9.05 g. of the mixture in about 25, cc. of pyridine, heating thesolution to about C..and adding thereto about 5.0 g. of succinic;anhydride. The mixture is heated at about95? C. c for approximately 15minutes additonal: time,;

about 5 cc. ofwater isadded to the hot solution to decompose excesssuccinic anhydride antithe pyridine is then evaporated therefrom under.re- -wduced pressure. The residual material is dissolved in chloroform,the chloroform solution is washed with dilute hydrochloric acid toremove traces of pyridine, then with water, and the hemisuccinates ofthe stereoisomeric 3,11-diketo- 20,21-dihydroxy-pregnanes are finallyextracted therefrom as their potassium salts, by means of a 10% aqueouspotassiumcarbonate solution.

The aqueous potassium carbonate extracts are combined, acidifed withdilute hydrochloric acid and extracted with chloroform. The chloroformextract is washed with water and evaporated to dryness under reducedpressure to produce about #2 g. of a mixture containing crude3,11-diketo- 20 (a) -hydroxy- 21 (5 carboxy apropionoxy) pregnane and3,11-diketo-20-(fi)-2l-(B-carboxypropionoxy) -pregnane. This mixture,containing about 7.2 g. of hemisuccinates is saponified by dissolving inabout '75 cc. of water containing about 1.3 g. of potassium bicarbonateand about 7.5 g. of potassium carbonate andheating the resultingsolution on the steam bath for approximately hour. The oily precipitateof dihydroxy-diketo-pregnanes and unsaponified potassium salts is thenredissolved by addition thereto of about cc. of a 1% methanolic sodiiunhydroxide solution. This solution is allowed to stand at about 20 C. forapproximately 18 hours, the solution is evaporated to small volume underreduced pressure, and extracted with chloroform. The, chloroform layeris washed with water and evaporated to dryness to produce about 5.2 g.of a crude mixture containing 3,11- diketo-20-(a) -2l-dihydroxy-pregnaneand 3,11-

diketQTZO-(fl)-21-dihydroxy-pregnane. I

Example 3 The crude mixture of stereoisomeric diketodihydroxy-pregnanesis separated by the following procedure: About 5.2 g. of thecrudemixture approximately hours. about 30 cc. of water is addedthereto andthe resulting solution evaporated to small volume under reducedpressure. is extracted with benzene and thebenzene extract .is washedsuccessively with dilute hydro-,- chloric acid, dilute aqueous potassiumcarbonate The benzene solution is" solution,- and water.

evaporated to dryness under reduced pressure'to produce about 6.2 g. ofa crude mixture'containing 3,1l-diketo-20-(a and ,B)-21-diacetoxypregnanes.

- dihydroxy .pregnane; :3

and:

-.2l-dihydroxy-pregnane;' L

The residual material These are separated chromatographically' bydissolving in benzene, adding petroleum ether to thebenzene solutionuntil the latter becomes turbid and then absorbing ona column of alumina9?" previously --aetivatedi by heating at 150i" C. The elution isconductedsbyadding successive portions flisclvent' mixtures, begmningwith 1:1-petroleum ether: ether, proceeding through higherconcentrations 'of ether to, pure ether and finally eluting withether-chloroform mixtures of increasing chloroform content. Each eluateis evaporated to dryness by' itseltand crystalline residues havingsimila-rproperties are combined.

The group eluatefs from 1:9 -petrole'um ether'zether up to and including6 :"4-ether: chloroform contains 3,11-diketo-20-(13),-2ledi-"acetoxy-pregnane which is purified by recrystallization from diluteacetone; P. 1'74=.5-1!7,5,.0 C. (corr-J; a =+74 (acetone). The groupel-uates from 6:4-etherrchloroform to 2 8-ether chloroform contains 3,11 -diketo-20- (c) -21-diacetoxy-pregnane. Recrystallization of the crudematerial from ethyl acetateyields the pure diacetate; M. (acetone).

The 3;l1-diketo-20-(/3) -21-diacetoxy-pregnane is saponified bydissolving about-490 mg. of'the compound in a mixture containing about20 cc. methanol, about cc. water, about 300 mg. potassium carbonate andabout 650 mg. potassium bicarbonate andallow-ing the resulting solutionto stand at about C. for approximately 22 hours. The resulting solutionis evaporated under reduced pressure to a small volume to produce acrystalline precipitate which is centrifuged, washed and purified byrecrystallization from a small volume of acetone, to producesubstantially pure 3,11-diketo-20-(m- 21-dihydroxypregnane; M. P.168-168.5 C. (corn); a =+6L5 (acetone).

A sample of the 3,11-diketo-20-(c)-21-diacetoxy-pregnane (M. P. 181 C.)prepared above is saponified in the manner described for the hydrolysisof the 20-(/8) -derivative, the product isolated and purified byrecrystallization from acetone as therein described to producesubstantially pure 3,11-dik8t0-20-(a) -dihydroxypregnane; M. P. 182-183"0. (corn) a =+68.5 (acetone).

Various changes and modifications may be made in the present inventionas described without departing from the spirit and scope thereof. To theextent that these changes and modifications are within the purview ofthe annexed claims, they are to be considered as part of my invention.

I claim:

1. The process which comprises reacting a mixture containing M-3,ll-diketo-pregnene and A -3,1l-diketo-pregnene with a compoundselected from the class which consists of osmium tetroxide and hydrogenperoxide to produce a mixture containing 3,1l-diketo-20-(a)-21-dihydroxy pregnane, 3,11 diketo 20 (,8) 21 dihydroxy-pregnane and3,1L-diketo-17,20-dihydroxy-pregnane; reacting this mixture with acyclic anhydride of a dicarboxylic acid to convert the 20,21-dihydroxycompounds to the corresponding 3,11 diketo 20 hydroxy 21(carboxy-acyloxy)-pregnanes admixed with unchanged3,11-dil:eto-17,20-dihydroxy-pregnane; separating the half esters fromthis mixture; hydrolyzing said half-esters to produce a mixture of thecorresponding 3,11-diketo-20,21- dyhydroxy-pregnanes substantiallyuncontaminated by the 17,20-dihydroxy isomer; reacting this mixture witha compound selected from the class which consists of benzoyl chloride,lower aliphatic carboxylic acid anhydrides and lower aliphaticcarboxylicacid halides, to produce a mixture containing thecorresponding 3,11;- diketo-20-(a)-21-diacyloxy-pregnane and 3,111-diketo-ZO-(p)-2l diacyloxy pregnane; and sepae rat'ing these isomers toproduce the individual stereoisomers, 3,'11'- diketo 20(c)1,21diacyloxy-pregnane and 3,11-diketo-29(,8)-,21-diacy loxy-pregnane.

2. The proce'sswhich comprises reacting a mix turev containing A-3,ll-diketo-pregnene and A 3,11 diketo--- lpregnene with osmiumtetroxide to produoaa mixture containing;=3-,11- diketo 20 (a) 21dihydroxy pregnane, 3,11 diketo 20 (,B') 21 dihydroxypregna-ne and 3,11diketo 17,20"--'dihydro xy preg; nane; rcacting'this mixture withsuccinicanhydride and pyridine to convert the 3,11.-.diketo,-20,21-dihydroxy-pregnane isomers 'to the corresponding 3,11 diketo20-hydroxy 21 (fircarbox-y-propion'oxy) -pregnanes admixed withunchanged 3,11 diketo. 17,20 dihydroxy.- pregnane; separating the halfesters from this mixture by selectiveextraction with an aqueous alkalinesolution, hydrolyzing said half-esters to produce a mixture of thecorresponding 3,11- diketo-20,2l dihydroxy-pregnanes. substantiallyuncontaminated bythe 17:,20-dihydroxy isomer; reacting thisstereoisomeric mixture of 3,11- diketo-20,2l -dihydroxy-pregnane withacetic anhydride andpyridiney'to produce a mixture containing 3,11-'diketo -20. (a) 21 diac'etoxy pregnane and 1 3,'11'-diketo+-20.-(Bl-21-diacetoxy pregnane and separating this mixture ofstereoisomers by chromatographic absorption to produce the individualstereoisomers, 3,11-diketo- 20-(a),21-diacetoxy-pregnane and3,11-diketo- 20- ([3) ,zl-diacetoxy-pregnane in substantially pure form.

3. The process which comprises reacting a cyclis anhydride of adicarboxylic acid with a mixture containing3,11-diketo-20,21-dihydroxypregnane and3,11-diketo-17,20-dihydroxy-pregnane to produce a mixture comprising thecorresponding 3,1 1-diketo-20-hydroxy-2 1 carboxyacyloxy) -pregnaneadmixed with unreacted 3,11- diketo-17,20-dihydroxy-pregnane, andseparating the 3,11-diketo-20-hydroxy-21-(carboxyacyloxy) -pregnane fromthis mixture.

4. The process which comprises reacting succinic anhydride and pyridinewith a mixture containing 3,11 diketo 20,21 dihydroxy pregnane and3,11-diketo-17,20-dihydroxy-pregnane to produce a mixture comprising3,11-diketo-20- hydroxy 21 (e carboxy propionoxy) pregnane admixed withunchanged 3,11-diketo- 17,2fi-dihydroxy pregnane, and separating the3,11 diketo 20 hydroxy 21 (5 carboxy propionoxy)-pregnane from thismixture by extracting a solvent solution of said mixture with an aqueousalkaline solution.

5. The process which comprises reacting 3,11-diketo-20,21-dihydroxy-pregnane with a cyclic anhydride of adicarboxylic acid to produce 3,11- diketo 20 hydroxy 21 (carboxyacyloxy) pregnane.

6. The process which comprises reacting a mixture containing3,11-dik8tO-20(a) ,21-dihydroxypregnane and3,11-diketo-20m),21-dihydroxypregnane with an excess of an acylatingagent to produce a mixture of the corresponding 3,11- diketo-2001),21-diacyloxy-pregnane and 3,11- diketo-ZOUR),21-diacyloxy-pregnane andseparating these compounds from each other by chromatographicadsorption.

'7. The process of preparing 3,11-diketo-20- 3,11- diketo 20(a),21diacetoxy pregnane and 3,11 diketo 20( 3),21 diacetoxy preg name; andseparating the desired 3,11-diketo-20- (cf-2l diacetoxy-pregnanefromsaid mixture by chromatographic absorption.

ill-The process of preparing 3,11-diketo-20-(B) 21-diacetoxy-pregnanefrom a mixture containing-3,11 diketo 20(11) ,21 dihydroxy pregnane and3,1l -diketo-20(p),21-dihydroxy-pregnane which comprises reacting saidmixture with an excess of acetic anhydride and pyridine to produce thecorresponding mixture containing 3,11 diketo 20(11) ,21 diacetoxypregnane --'.nd 3,11 diketo 20(p),21 diacetoxy pregnane; and separatingthe desired 3,11-diketo-20- (5) zl-diacetoxy-pregnane from said mixtureby chromatographic absorption.

v 9. 3,11-diketo-20,ZI-dihydrcxy-pregnane.

10, 3,11-diketo-20-( 8)-21-dlihydroxy-pregnane having, when insubstantially pure form, a melting point of about 168 0., and an aapproximately equal to 65 in acetone. 11. 21 substituted-3,11 diketo 20hydroxypregnanes in which the substituent in the 21- position has theformula RCOO-, wherein R is a beta-carboxy-substituted lower alkylradical.

12. 3,11 diketo 20 hydroxy 21 (B- carboxy-propionoxy) -pregnane.

13. 3,11-diketo-20- (18) -21-diacetoxy-pregnane having, when insubstantially pure form, a melting point of about C., and an (1approximately equal to +74? in acetone.

14. 3,11-diket0-20,21-diacetoxy-pregnane;

15. The process which comprises reacting 3,11-diketo-20,2l-dihydroxy-pregnane with succinic anhydride and pyridine toproduce 3,11-diketo- 20 hydroxy 21- (3 carboxy propionoxy) pregnane.

16, Lower aliphatic carboxylic acid esters of20,21-dihydroxy-3,ll-diketo-pregnane. I

' LEWIS H. SARETI.

REFERENCES CITED The following references are of record in the file ofthis patent:

UNITED STATES PATENTS- FOREIGN PATENTS Country Date France 1 May 10,193?

Number Number

1. THE PROCESS WHICH COMPRISES REACTING A MIXTURE CONTAINING$**20,21-3,11-DIKETO-PREGNENE AND $**17,20-3,11-DIKETO-PREGNENE WITH ACOMPOUND SELECTED FROM THE CLASS WHICH CONSISTS OF OSMIUM TETROXIDE ANDHYDROGEN PEROXIDE TO PRODUCE A MIXTURE CONTAINING 3,11 - DIKETO -20-(A)-21-DIHYDROXY - PREGNANE, 3,11 - DIKETO - 20 - (B) - 21DIHYDROXY-PREGNANE AND 3,11-DIKETO-17,20-DIHYDROXY-PREGNANE; REACTINGTHIS MIXTURE WITH A CYCLIC ANHYDRIDE OF A DICARBOXYLIC ACID TO CONVERTTHE 20,21-DIHYDROXY COMPOUNDS TO BE CORRESPONDING 3,11 - DIKETO - 20 -HYDROXY - 21 - (CARBOXY-ACYLOXY)-PREGNANES ADMIXED WITH UNCHANGED3,11-DIKETO-17,20-DIHYDROXY-PREGNANE; SEPARATING THE HALF ESTERS FROMTHIS MIXTURE; HYDROLYZING SAID HALF-ESTERS TO PRODUCE A MIXTURE OF THECORRESPONDING 3,11-DIKETO-20,21DIHYDROXY-PREGNANES SUBSTANTIALLYUNCONTAMINATED BY THE 17,20-DIHYDROXY ISOMER; REACTING THIS MIXTURE WITHA COMPOUND SELECTED FROM THE CLASS WHICH CONSISTS OF BENZOYL CHLORIDE,LOWER ALIPHATIC CARBOXYLIC ACID ANHYDRIDES AND LOWER ALIPHATICCARBOXYLIC ACID HALIDES, TO PRODUCE A MIXTURE CONTAINING THECORRESPONDING 3,11DIKETO-20-(A)-21-DIACYCLOXY-PREGNANE AND3,11DIKETO-20-(B)-21-DIACYLOXY PREGNANE; AND SEPARATING THESE ISOMERS TOPRODUCE THE INDIVIDUAL STEREOISOMERS, 3,11 - DIKETO - 20(A),21 -DIACYLOXY-PREGNANE AND 3,11 - DIKETO - 20(B),21-DIACYLOXY-PREGNANE.